The studies proposed in this application will investigate cell membrane phenomena that may be related to the occurence of affective disorders, or to the treatment of such disorders with lithium (Li+). These studies will utilize the RBC membrane in a selective way as a model for certain aspects of membrane functioning. The first component of the investigation will be performed with carefully diagnosed (by RDC criteria), drug-free subjects from the following clinical categories: unipolar depressed; unipolar recovered; bipolar depressed; bipolar hypomanic; and control (new affectively ill). Current symptomatology will be assessed by means of observer- and self- administered clinical rating scales. The specific aims for this part of the project are to investigate the following biological areas in relation to clinical affective status: 1) modulatroy and intrinsic aspects of RBC membrane sodium (Na+) transport via the Na+-K+ pump; 2) carrier-mediated RBC membrane choline (Ch+) transport; and 3) RBC membrane composition of Ch+-, amino-, and inositol-phospholipids. Possible interrelationships among these various bilogical areas, as well as their relationships to clinical affective status, will be assessed. By collecting a variety of clinical and biological data from subjects representing several distinct diagnostic categories and clinical affective states, the project will attempt to develop a clearer understanding of membrane phenomena in relation to affective illness. In the second component of the investigation, hypomanic bipolar patients who have participated in the first component will be studied during Li+ treatment, in order to measure both Li+- induced membrane changes and therapeutic outcome. Specifically, the project will investigate treatment-related effects on RBC Na+ influx, plasma modulation of the Na+-K+ pump, membrane Ch+ transport, kinetic parameters of Na+-Li+ countertransport, and RBC membrane composition of Ch+-, amino- and inositol-phospholipids. Clinical and biological measurements will be performed prior to treatment, and will be repeated after 1, 2, and 4 weeks of Li+ therapy. In this way, the project will attempt to determine whether changes in one or more of these potentially interrelated membrane parameters are associated with corresponding changes in clinical affective state during Li+ treatment. The proposed research project might eventually lead to a better understanding of biological mechanisms in affective illness, or to new biological strategies for predicting treatment responsiveness.